P509: THE IMPACT OF THE NUMBER OF RAS MUTATIONS IN THE OUTCOMES OF PATIENTS WITH ACUTE MYELOID LEUKEMIA TREATED FRONTLINE AT A SINGLE INSTITUTION.
Authors: Mahesh Swaminathan, Rashmi Kanagal-Shamanna, Farhad Ravandi, Tapan Kadia, Courtney Dinardo, Naval Daver, Naveen Pemmaraju, Elias Jabbour, Sherry Pierce, John Matthew Villareal, Gautam Borthakur
Journal: HemaSphere (2023)

Background: Mutations in the RAS gene occurs in ~10-15% of patients with untreated AML and are considered to appear at the later stages of leukemogenesis. The current European LeukemiaNet (ELN) 2022 risk stratification does not include RAS. It is common for some patients to have more than one RAS mutation at diagnosis, which may indicate clonal heterogeneity/interference. Among core binding factor AML, the presence of clonal heterogeneity based on RAS mutation has been associated with worse outcomes. Whether the number of RAS mutations impacts the outcomes of newly diagnosed AML patients treated with frontline regimens is unknown. We performed a retrospective single-institution study to answer this question. Aims: To understand the impact of the number of RAS mutations in the outcomes of patients with AML treated with frontline regimens at MD Anderson Cancer Center. Methods: We included all adult patients with AML who received frontline treatment at MD Anderson Cancer Center from January 2013 to December 2021. All patients had next-generation sequencing (NGS) performed from the bone marrow aspiration sample at the start of frontline treatment. The sensitivity of the assay is 5%. Patients were stratified into 2 groups based on the number of RAS mutations (1 vs. ≥2). All patients were classified based on ELN 2022 AML risk classification. Responses and survival were defined by the modified Cheson criteria. Survival outcomes were assessed using Kaplan-Meier estimates, and the log-rank test was used to analyze the differences between the groups. Results: 1461 patients were found to have mutations in the RAS-MAP kinase pathway. Among them, 261 patients were identified to have RAS-mutated untreated AML and were included in the study. Of them, 202 (77%) patients had one RAS mutation, and 59 (23%) had ≥2 RAS mutations. The median age was 63 years (20-84) vs. 64 (22-85). Over half of the patients received low-intensity treatment because of age. As per ELN 2022 AML risk stratification, 11% vs. 7% were favorable, 52% vs. 39% were intermediate, and 37% vs. 54% were adverse risks. The median overall survival (OS) was significantly longer in patients with one RAS mutation (17 vs.10 months, p=0.0011). Similarly, the median relapse-free survival (RFS, uncensored for stem cell transplant) was 14 months in patients with one RAS mutation compared to 9 months, p=0.0233 (Figure 1). Among patients with one RAS mutation, there was a significant difference in the median OS when stratified by ELN 2022 risk groups (48 vs. 32 vs. 22 months, p=0.005). However, there was no difference in the median RFS (p=0.239). Interestingly, there was no difference in the median OS or RFS among patients with ≥2 RAS mutations (p=0.212 vs. p=0.493, respectively). When we compared patients with one vs. ≥2 RAS mutations: the median OS was significantly longer in patients with one RAS mutation regardless of ELN risk type (p=0.0003). Similarly, there was a trend to a longer median RFS in patients with one RAS mutation (p=0.074). Patients treated with intensive therapy had significantly longer median OS and RFS in patients with one RAS mutation (p=<0.001 and p=0.003, respectively) but not in patients with ≥2 RAS mutations (p=0.466 and p=0.696, respectively). Summary/Conclusion: Our data suggest that the number of RAS mutations impacts the OS adversely regardless of the associated chromosomal or genomic aberrations (included in ELN 2022 risk stratification). Prospective studies are needed to validate this observation. Figure 1Keywords: Ras, Acute myeloid leukemia, AML